While the progress in identifying major cancer susceptibility genes has been gratifying, our ability to intervene at the molecular level in order to reduce the risk associated with mutations in these genes is embryonic. We are in urgent need of safe and effective strategies through which the risk of cancer in mutation carriers can be reduced now. A strategic planning process within DCEG led to a recommendation that the Division expand its activities in the area of intervention studies, a proposal which has been endorsed by the Intramural Division Directors. National Ovarian Cancer Prevention and Detection Study Among the many pressing clinical issues in the management of women who carry mutations in BRCA1/2 is the appropriate role of prophylactic oophorectomy as a risk reduction strategy. In collaboration with investigators from the Gynecologic Oncology Group (GOG) and the Cancer Genetics Network (CGN), a national, prospective follow-up study of genetically at-risk women who elect to undergo risk-reducing salpingo-oophorectomy (RRSO) has been launched (NCI Protocol #02-C-0268; GOG-199). Dr. Greene is the National Study Chair for this protocol, which is addressing the following issues: (a) What is the prevalence of clinically occult ovarian cancer at the time of risk-reducing surgery? (b) Are there identifiable precursor lesions in the ovaries of genetically at-risk women? (c) What is the incidence of primary peritoneal carcinomatosis and breast cancer subsequent to RRSO? and (d) How does this surgical procedure affect the quality of life and morbidity from non-oncologic medical conditions for the women who elect it? Women who elect to retain their ovaries are being screened with a novel ovarian cancer screening algorithm based on longitudinal changes of CA125 (and other tumor marker) levels over time. This study opened to accrual in the summer of 2003, and is presently accruing patients at 157 GOG sites in the United States and Australia. Currently, 2249 subjects have enrolled on the trial (accrual target: 2332), including 904 surgical and 1345 screening subjects. The study will close to new patient accrual on November 1, 2006. The very large task of BRCA1/2 mutation testing has begun, in order to determine the mutation status of the 60% of study participants who have not undergone prior clinical genetic testing. These data will be a critical stratification variable in the final study analysis. We are in the midst of finalizing a pilot study to assess the feasibility of harvesting ovarian surface epithelial cells from the ovaries that are removed to reduce the genetic risk of ovarian cancer in GOG-199. We are evaluating whether these cells can be used for cytology, genomic and proteomic analyses. Early data are encouraging. The data analysis targeting the medical decision-making process (regarding how women selected either surgery or screening) is in manuscript preparation. Data obtained from the first 600 study participants at the time of study entry have been used to build a predictive model; the model will then be tested/validated using data from the next cohort of 1400 subjects. Additional ancillary analyses in various stages of planning include: (1) an evaluation of baseline Quality-of-Life meansures in each of the two study groups; (2)a quantitative evaluation of factors which influence serum levels of CA-125 obtained at study entry, pooling data from the screening arms of GOG-199 and the companion CGN screening study (designated "the ROCA Trial"). (3) a detailed description of the standard light microscopy, H&E-stained histologic characteristics of fallopian tube mucosa and ovarian surface epithelium and stroma in RRSO-derived surgical material.(4) a multidisciplinary, laboratory-based assessment of the molecular biologic characteristics of ovarian and fallopian tube tissue obtained from high-risk women at the time of RRSO.